PHARMACOKINETICS OF HEPARIN AND OF DERMATAN SULFATE: CLINICAL IMPLICATIONS B. Boneu, C. Caranobe, S. Saivin, F. Dol,
p. Sie
Laboratoire d'Hemostase Centre de Transfusion Sanguine 31052 Toulouse Cedex, France INTRODUCTION The pharmacokinetic data concerning heparin and dermatan sulfate are usually based upon the disappearance of the biological activities generated after parenteral administration, and not upon the direct determination of their chemical concentrations. At least for heparin, these biological activities are mainly related to the polysaccharide chain length and to the antithrombin III affinity, two factors which largely influence heparin clearance. A good understanding of the pharmacokinetic properties of these glycosaminoglycans needs several complementary approaches which may provide conflicting results reflecting the functional and structural heterogeneity of these compounds. PHARMACOKINETICS OF UNFRACTIONATED HEPARIN (UH) After parenteral administration of trace amounts of radiolabeled heparin to animals, the radioactivity is first concentrated in the liver, spleen, bone marrow and lungs. Desulfated and depolymerised material is then excreted in the urine (1). Histochemical methods allow UH to be identified in the endothelial and the reticulo-endothelial cells (2, 3). The blockade of the phagocytic capacities of the reticulo-endothelial system by dextran sulfate dramatically prolongs the half life of UH injected intravenously (4). UH also binds to endothelial cells in culture, a phenomenon independent of the antithrombin III affinity (5-7). Almost 30 % of bound UH is internalized and depolymerised by lysosomal enzymes (8). This cell compartment represents the saturable mechanism of clearance which is pre-eminent for the elimination of the doses usually prescribed in clinical practice. At higher doses, the clearance capacities of this mechanism reach a maximum and the excess of heparin which can not be metabolized is excreted as undegraded and still active material in the urine (1, 4, 9). This model allows the major pharmacokinetic properties of unfractionated heparin to be understood. After bolus intravenous injection, the biological activities of heparin are cleared exponentially with a progressive prol~ngation of the half-life when the dose increases (10-12). Over 100IU.Kg- the disappearance of the biological activity follows a concave-convex pattern, which is typical of a saturable-non saturable mechanism of clearance (12, 13). In the rabbit (12), we have established that D. A. Lane et al. (eds.), Heparin and Related Polysaccharides © Springer Science+Business Media New York 1992
237
Table 1. Half-Lives (min) of 1251 Heparin and of 1251_CY216 After Bolus Intravenous Injection of Various Doses to Rabbits Dose injected
unfractionated
Anti Xa IU.Kg-1
heparin
1.5 2.5 5 10 25 50 100 250 375 500
3.8 4.3 7.9 8.9 14.7 32.0 24.0 30.0
CY216 8.1 9.2 9.8 9.6 11.0 12.5 12.9
These data are taken from ref. 16. Trace amounts of radiolabeled UH and CY 216 were injected to animals with increasing doses of unlabeled material. Blood was taken at time intervals to determine the circulating radioactivity. The curves obtained were decomposed into 3 exponentials (alpha. beta. gamma). The beta phase half-life was found to be dose-dependent for UH and almost constant for CY 216. there is almost 10 fold difference ~etween the half-Yfe and the clearance calculated after injection of 5IU.kg- and 250IU.kg- (Table 1). Over this dose. i.e. after saturation of the cellular mechanism of clearance. there is no further change in the pharmacokinetic parameters. Moreover. we have shown that after bolus intravenous injection the instantaneous half-life continuously shortens as the plasma concentration decreases; this accounts for the convexity of the last part of the curve (Fig 1). The non-linearity of the pharmacokinetic parameters also explains the apparent low bioavailability of UH. roughly 30 %. when delivered subcutaneously at low doses to prevent deep vein thrombosis. We hypothesized that. at any dose. the bioavailability of heparin was in fact close to 100 % (14). The bioavailability of heparin injected by subcutaneous route reflects the amount which enters the plasma compartment from the subcutaneous depot and the velocity at which it disappears from the plasma. Since the plasma concentrations generated are lower following subcutaneous compared with intravenous injection. the amounts of UH delivered by the subcutaneous route are cleared more rapidly by the saturable mechanism which continuously shortens the half-life as the plasma concentration declines (12). The relative importance of this dosedependent effect decreases as the dose delivered by the subcutaneous route increases. i. e. when plasma UH concentrations generated are higher and when the cellular mechanism of clearance is saturated (Fig 2). FACTORS HEPARIN
INFLUENCING
THE
PHARMACOKINETIC
BEHAVIOR
OF
The pharmacokinetic behavior of the polysaccharide chains of heparin may be altered by the molecular weight. the affinity to antithrombin III and the non-specific binding to plasma proteins. Clinical experience indicates that other unidentified factors may significantly modulate the pharmacokinetic properties of heparin.
238
10
• SH
oCY216
~ 5
....::::I
...... 2
>-
~
1
i=
~ .5
p. Sie
Laboratoire d'Hemostase Centre de Transfusion Sanguine 31052 Toulouse Cedex, France INTRODUCTION The pharmacokinetic data concerning heparin and dermatan sulfate are usually based upon the disappearance of the biological activities generated after parenteral administration, and not upon the direct determination of their chemical concentrations. At least for heparin, these biological activities are mainly related to the polysaccharide chain length and to the antithrombin III affinity, two factors which largely influence heparin clearance. A good understanding of the pharmacokinetic properties of these glycosaminoglycans needs several complementary approaches which may provide conflicting results reflecting the functional and structural heterogeneity of these compounds. PHARMACOKINETICS OF UNFRACTIONATED HEPARIN (UH) After parenteral administration of trace amounts of radiolabeled heparin to animals, the radioactivity is first concentrated in the liver, spleen, bone marrow and lungs. Desulfated and depolymerised material is then excreted in the urine (1). Histochemical methods allow UH to be identified in the endothelial and the reticulo-endothelial cells (2, 3). The blockade of the phagocytic capacities of the reticulo-endothelial system by dextran sulfate dramatically prolongs the half life of UH injected intravenously (4). UH also binds to endothelial cells in culture, a phenomenon independent of the antithrombin III affinity (5-7). Almost 30 % of bound UH is internalized and depolymerised by lysosomal enzymes (8). This cell compartment represents the saturable mechanism of clearance which is pre-eminent for the elimination of the doses usually prescribed in clinical practice. At higher doses, the clearance capacities of this mechanism reach a maximum and the excess of heparin which can not be metabolized is excreted as undegraded and still active material in the urine (1, 4, 9). This model allows the major pharmacokinetic properties of unfractionated heparin to be understood. After bolus intravenous injection, the biological activities of heparin are cleared exponentially with a progressive prol~ngation of the half-life when the dose increases (10-12). Over 100IU.Kg- the disappearance of the biological activity follows a concave-convex pattern, which is typical of a saturable-non saturable mechanism of clearance (12, 13). In the rabbit (12), we have established that D. A. Lane et al. (eds.), Heparin and Related Polysaccharides © Springer Science+Business Media New York 1992
237
Table 1. Half-Lives (min) of 1251 Heparin and of 1251_CY216 After Bolus Intravenous Injection of Various Doses to Rabbits Dose injected
unfractionated
Anti Xa IU.Kg-1
heparin
1.5 2.5 5 10 25 50 100 250 375 500
3.8 4.3 7.9 8.9 14.7 32.0 24.0 30.0
CY216 8.1 9.2 9.8 9.6 11.0 12.5 12.9
These data are taken from ref. 16. Trace amounts of radiolabeled UH and CY 216 were injected to animals with increasing doses of unlabeled material. Blood was taken at time intervals to determine the circulating radioactivity. The curves obtained were decomposed into 3 exponentials (alpha. beta. gamma). The beta phase half-life was found to be dose-dependent for UH and almost constant for CY 216. there is almost 10 fold difference ~etween the half-Yfe and the clearance calculated after injection of 5IU.kg- and 250IU.kg- (Table 1). Over this dose. i.e. after saturation of the cellular mechanism of clearance. there is no further change in the pharmacokinetic parameters. Moreover. we have shown that after bolus intravenous injection the instantaneous half-life continuously shortens as the plasma concentration decreases; this accounts for the convexity of the last part of the curve (Fig 1). The non-linearity of the pharmacokinetic parameters also explains the apparent low bioavailability of UH. roughly 30 %. when delivered subcutaneously at low doses to prevent deep vein thrombosis. We hypothesized that. at any dose. the bioavailability of heparin was in fact close to 100 % (14). The bioavailability of heparin injected by subcutaneous route reflects the amount which enters the plasma compartment from the subcutaneous depot and the velocity at which it disappears from the plasma. Since the plasma concentrations generated are lower following subcutaneous compared with intravenous injection. the amounts of UH delivered by the subcutaneous route are cleared more rapidly by the saturable mechanism which continuously shortens the half-life as the plasma concentration declines (12). The relative importance of this dosedependent effect decreases as the dose delivered by the subcutaneous route increases. i. e. when plasma UH concentrations generated are higher and when the cellular mechanism of clearance is saturated (Fig 2). FACTORS HEPARIN
INFLUENCING
THE
PHARMACOKINETIC
BEHAVIOR
OF
The pharmacokinetic behavior of the polysaccharide chains of heparin may be altered by the molecular weight. the affinity to antithrombin III and the non-specific binding to plasma proteins. Clinical experience indicates that other unidentified factors may significantly modulate the pharmacokinetic properties of heparin.
238
10
• SH
oCY216
~ 5
....::::I
...... 2
>-
~
1
i=
~ .5
